Preparation and characterization of some substituted benzyl n-nitrosocarbamates containing an n-2-(methylthio)ethyl or a bis(2-aminoethyl)sulfide functionality

Article abstract of DOI:10.1080/00397910802527755

The synthesis and characterization of some substituted benzyl N-nitrosocarbamates with an N-2-(methylthio)ethyl or a bis(2-aminoethyl)sulfide functionality is reported, as a part of a long-term goal to design and prepare novel photolabile structures that could be used as substances for controlled release of alkylating and/or crosslinking agents. The synthesis was accomplished by reaction of benzyl chloroformates with the corresponding amines, resulting in the preparation of carbamates. The latter were subsequently nitrosated, utilizing two different N-nitrosation methods, to yield the target structures.

Full text of DOI:10.1080/00397910802527755

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Preparation and
Characterization of Some
Substituted Benzyl N-
Nitrosocarbamates Containing
an N-2-(Methylthio)ethyl or
a Bis(2-aminoethyl)sulfide
Functionality
Satya Venkata a , Eric Shamo a & Vladimir Benin a
a Department of Chemistry, University of Dayton,
Dayton, Ohio, USA
Published online: 19 Mar 2009.
To cite this article: Satya Venkata , Eric Shamo & Vladimir Benin (2009) Preparation
and Characterization of Some Substituted Benzyl N-Nitrosocarbamates Containing
an N-2-(Methylthio)ethyl or a Bis(2-aminoethyl)sulfide Functionality, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:8, 1406-1414, DOI: 10.1080/00397910802527755
To link to this article: http://dx.doi.org/10.1080/00397910802527755
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Synthetic Communications1, 39: 1406–1414, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802527755
Preparation and Characterization of Some
Substituted Benzyl N-Nitrosocarbamates
Containing an N-2-(Methylthio)ethyl or
a Bis(2-aminoethyl)sulfide Functionality
Satya Venkata, Eric Shamo, and Vladimir Benin
Department of Chemistry, University of Dayton, Dayton, Ohio, USA
Abstract: The synthesis and characterization of some substituted benzyl
N-nitrosocarbamates with an N-2-(methylthio)ethyl or a bis(2-aminoethyl)sulfide
functionality is reported, as a part of a long-term goal to design and prepare novel
photolabile structures that could be used as substances for controlled release
of alkylating and=or crosslinking agents. The synthesis was accomplished by
reaction of benzyl chloroformates with the corresponding amines, resulting in
the preparation of carbamates. The latter were subsequently nitrosated, utilizing
two different N-nitrosation methods, to yield the target structures.
Keywords: Carbamates, 2-(methylthio)ethyl group, N-nitrosation, N-nitroso-
carbamates
INTRODUCTION
In recent years, a considerable amount of effort in drug design has been
focused on the development of drugs that are supposed to release their active
species in the desired locality and=or conditions and also on identifying
structures with photosensitive groups that would cleave upon irradiation
with near ultraviolet (UV) or visible light, yielding active intermediates for
biological applications.[1] First reported by Barltrop and Schofield in
Received August 21, 2008.
Address correspondence to Vladimir Benin, Department of Chemistry, Univer-
sity of Dayton, 300 College Park, Dayton, OH 45469-2357, USA. E-mail: vladimir.
benin@notes.udayton.edu
1406

Substituted Benzyl N-Nitrosocarbamates
1407
Figure 1. Target structures containing the N-2-(methylthio)ethyl (1) or the
bis(2-aminoethyl)sulfide (2) functionality.
1962.[2] photolabile protecting groups have found numerous applications in
biology in the past decade.[3,4] The protecting groups (also known as
‘‘caging’’ groups) can render a bioactive compound inert until they are
removed by photolysis, thus releasing the compound rapidly. Some
examples of commonly used photolabile caging groups include the
o-nitrobenzyl,[5] desyl,[6] and 2-methoxy-5-nitrophenyl (MNP).[7] However,
the commonly employed 2-nitrobenzyl photosensitive protecting group
has found limited use in compounds destined for biochemical systems,
because of the release of a toxic by-product: 2-nitrobenzaldehyde.[8,9]
Zimmerman first demonstrated the efficient photosolvolysis of benzyl
acetate in 50% aqueous dioxane.[10] His studies showed that the process
occurred in a homolytic fashion and led to radical-derived products: 4,40-
dimethoxybibenzyl and 4-methoxybenzyldioxane. However, a more recent
study of Ruane et al. on the photocleavage of substituted benzyl diazenium-
diolatesdemonstrated thatthe nature of the cleavage process depended on the
pattern of substitution in the benzylic group.[11] It was found that compounds
with p-donor substituent groups at the 3- and 5-positions of the benzene ring
tended to decompose via heterolytic, rather than homolytic bond cleavage,
and generate resonance-stabilized (in the excited state) benzylic carbocations.
Based on the demonstrated potential of substituted benzylic moieties
as photolabile protecting groups, we endeavored to design and prepare
several substituted benzyl N-nitrosocarbamates, with the longer-term
goal of developing a new class of anticancer agents, capable of releasing
the active substance photolytically, in controlled conditions. In the
current report, we describe the synthesis and characterization of two
sets of structures containing the N-2-(methylthio)ethyl (1) or the
bis(2-aminoethyl)sulfide (2) functionality (Fig. 1).
RESULTS AND DISCUSSION
Preparation of Benzyl N-2-(Methylthio)ethyl-N-nitrosocarbamates (1)
The preparation of these structures was carried out via the correspond-
ing carbamates, as reflected in Scheme 1. 2-(Methylthio)ethylamine,

1408
S. Venkata, E. Shamo, and V. Benin
Scheme 1. Preparation of benzyl N-2-(methylthio)ethyl-N-nitrosocarbamates.
prepared according to the protocol of Clarck and McAlees,[12] was reacted
with the corresponding benzyl chloroformate in the presence of an equiva-
lent amount of triethylamine in ether, following the procedure of Sato
et al.[13] The reaction led to the generation of the carbamate, 4a or 4b, in
moderate yield. The resultant carbamate structures were further nitrosated
to yield the N-nitrosocarbamates 1a,b. We did not expect the presence of a
sulfide group to pose problems in the nitrosation step, as there
are no known examples of S-nitrosation of sulfides that yield stable
S-nitroso products.[14] Our density functional theory (DFT) calculations
(B3LYP=6–31 þ G(d)) could not locate an energy minimum for an S-nitro-
socarbamate derivative, but a structure was identified that corresponds to
the intermediate for an S- to N-nitroso rearrangement. Such S- to N-nitroso
rearrangements have also been suggested to occur both inter- and intra-
molecularly in other reactions, such as the N-nitrosation of dimethylsulfide[15]
or the de-amination of methionine and S-methyl cysteine.[16]
The N-nitrosation was achieved by following one of two different
methods: Method 1 (aqueous method)[17] involved a two-phase (water–ether)
system, with the nitrosating agent, þNO, generated in the aqueous layer,
upon reaction of NaNO2 with HNO3. Method 2 (anhydrous method)[18]
involved the use of nitrosonium tetrafluoroborate (NOBF4) as a nitrosating
agent in the presence of a pyridine base, in anhydrous acetonitrile.
Preparation of Bis[(N-benzyloxycarbonyl-N-nitroso)aminoethyl]-
sulfides (2)
The preparation of these structures was conducted in accordance with
the synthetic sequence reflected in Scheme 2. Bis(2-aminoethyl)sulfide,
prepared from the hydrobromide salt of 2-bromoethylamine,[19]
was reacted with a benzyl chloroformate (3a,b) to generate the

Substituted Benzyl N-Nitrosocarbamates
1409
Scheme 2. Preparation of bis[(N-benzyloxycarbonyl-N-nitroso)aminoethyl]-
sulfides.
corresponding carbamate (5a,b). The carbamates were subsequently
nitrosated, using the anhydrous method (method 2), to yield the target
structures 2a,b.
CONCLUSIONS
In the current report, we have described in detail the preparation and
characterization of two sets of structures, which could be classified as
N-nitrosocarbamates or bis(N-nitrosocarbamates). All compounds have
been designed to contain either an N-2-(methylthio)ethyl or a bis(2-
aminoethyl)sulfide functionality. The target structures were prepared via
the corresponding carbamates or bis(carbamates) as precursors and
subsequent N-nitrosation, following an aqueous or anhydrous method.
EXPERIMENTAL
1H NMR and 13C NMR spectra of all compounds have been recorded at
300 MHz and 75 MHz respectively and referenced to the solvent (CDCl3:
7.27 ppm and 77.0 ppm; acetonitrile-d3: 1.93 ppm and 118.6 ppm).
Elemental analysis was provided by Atlantic Microlab, Norcross, GA.
High-resolution mass spectrometry (HRMS) data was provided by the
Mass Spectrometry and Proteomics facility at the Ohio State University.
Carbamates 4a and 4b are known compounds.[13,20,21] Nevertheless, their
syntheses, based on the slightly modified protocol of Sato et al.,[13] are
reported here to make available additional NMR data. 2-(Methylthio)-
ethylamine and bis(2-aminoethyl)sulfide were prepared following pub-
lished literature procedures. Benzyl chloroformate and 4-nitrobenzyl
chloroformate were purchased from Acros Organics. Nitrosonium
tetrafluoroborate was purchased from Fluka.

1410
S. Venkata, E. Shamo, and V. Benin
General Procedure for the Preparation of Benzyl
N-2-(Methylthio)ethylcarbamates (4a,b)[13]
A solution of 2-(methylthio)ethylamine (2.90 g, 31.83 mmol) in ether
(20 mL) was stirred for 5 min followed by addition of methylene chloride
(5 mL). Triethylamine (3.22 g, 31.83 mmol, 4.43 mL) was added, and the
solution was stirred for 10 min at 0 ꢀC under nitrogen. Benzyl chlorofor-
mate (3a, 0.54 g, 3.18 mmol, 0.45 mL) or 4-nitrobenzyl chloroformate (3b,
0.68 g, 3.18 mmol) in ether (10 mL) was added dropwise to the mixture for
about 30 min. The mixture was stirred 24 h at ambient temperature and
vacuum filtered, and the solvent evaporated under reduced pressure.
The residue was further separated, and the product was purified by col-
umn chromatography on silica gel.
Benzyl N-2-(Methylthio)ethylcarbamates (4a)
Isolated by separation of the crude reaction mixture on a silica-gel col-
umn (hexane–methylene chloride ¼ 1:1, followed by pure methylene
1
chloride). Yield: 0.28 g (42%) of colorless oily liquid. H NMR (CDCl3)
d 2.14 (s, 3H), 2.62 (t, J ¼ 6.3 Hz, 2H), 3.38 (m, 2H), 5.15(s, 2H), 5.28
(broad s, 1H) 7.30–7.38 (m, 5H). 13C NMR (CDCl3) d 15.3, 30.4, 39.4,
69.8, 128.5, 128.7, 128.9, 134.4, 153.7. HRMS (FABþ) m=z calcd. for
C11H15NO2S [M þ Na]þ 248.0721; found 248.0721.
4-Nitrobenzyl N-2-(Methylthio)ethylcarbamate (4b)
Isolated by separation of the crude reaction mixture on a silica-gel column
(hexane–ethyl acetate ¼ 2:1). Yield: 0.30 g (36%) of bright yellow solid: Mp
61–63 ꢀC (lit.[13] 63–64 ꢀC). 1H NMR (CDCl3) d 2.12 (s, 3H), 2.68 (t,
J¼ 6.3 Hz, 2H), 3.42–3.44 (t, J ¼ 6.3 Hz, 2H), 5.18 (s, 2H), 5.21 (broad s,
1H), 7.53 (d, J¼ 8.7 Hz, 2H), 8.24 (d, J¼ 8.7 Hz, 2H). 13C NMR (CD3CN)
d 15.5, 34.7, 41.0, 65.9, 124.9, 129.2, 146.4, 148.8, 157.3. Anal. calcd. for
C11H14N2O4S: C, 48.88; H, 5.22; N, 10.36. Found: C, 49.07; H, 5.31; N, 10.19.
General Procedure for the Preparation of Benzyl N-2-(Methylthio)-
ethyl-N-nitrosocarbamates (1a,b)
Method 1 (Aqueous Method)
A mixture of sodium nitrite (1.37 g, 19.92 mmol) in water (4 mL) was
added to a solution of benzyl N-2-(methylthio)ethylcarbamate (4a,

Substituted Benzyl N-Nitrosocarbamates
1411
0.50 g, 2.22 mmol) or 4-nitrobenzyl N-2-(methylthio)ethylcarbamate (4b,
0.60 g, 2.22 mmol) in ether (4 mL). Without stirring or cooling, nitric acid
(2.66 mL, 35% aq. sol.) was added directly to the lower layer over 1 h via
syringe. Then 8 mL of water and 8 mL of ether were added, the organic
layer was separated and dried (MgSO4), and the solvent was removed
under reduced pressure to yield the corresponding benzyl N-2-
(methylthio)ethyl N-nitrosocarbamate (1a,b). Further purification was
achieved by column chromatography on silica gel.
Method 2 (Anhydrous Method)
Solid nitrosonium tetrafluoroborate (NOBF4) (0.82 g, 7.09 mmol) was
added in one portion to a stirred solution of anhydrous pyridine (0.56 g,
7.09 mmol, 0.57 mL) and benzyl N-2-(methylthio)ethylcarbamate (4a,
1.00 g, 4.73 mmol) or 4-nitrobenzyl N-2-(methylthio)ethylcarbamate
(4b, 1.28 g, 4.73 mmol), in anhydrous acetonitrile (10 mL) at ꢁ20 ꢀC.
The mixture was stirred at 0 ꢀC under nitrogen for 2 h, and the progress
of the reaction was monitored by thin-layer chromatography (TLC,
hexane–methylene chloride ¼ 1:1). The product exhibited a rapidly mov-
ing yellow spot. The solvent was removed under reduced pressure, and
the product was purified by column chromatography on silica gel of
the crude reaction mixture.
Benzyl N-2-(Methylthio)ethyl-N-nitrosocarbamate (1a)
Purified by separation of the crude reaction mixture on a silica-gel
column (hexane–methylene chloride ¼ 1:1). Yields: 44% (method 1) and
1
43% (method 2) of light yellow liquid. H NMR (CDCl3) d 2.10 (s, 3H),
2.46 (t, J ¼ 6.3 Hz, 2H), 3.95 (m, 2H), 5.52 (s, 2H), 7.35–7.41 (m, 5H).
13C NMR (CDCl3) d 15.3, 30.4, 39.4, 69.8, 128.5, 128.7, 128.9, 134.4,
153.7. HRMS (FABþ) m=z calcd. for C11H14N2O3S [M þ Na]þ
277.0623; found 277.0628.
4-Nitrobenzyl N-2-(Methylthio)ethyl-N-nitrosocarbamate (1b)
Purified by separation of the crude reaction mixture on a silica-gel column
(hexane–ethyl acetate ¼ 1:2). Yields: 35% (method 1) and 38% (method 2)
of light yellow liquid. 1H NMR (CD3CN) d 2.11 (s, 3H), 2.51 (t, J ¼ 6.3 Hz,
Hz, 2H), 3.95 (t, J ¼ 6.3 Hz, 2H), 5.61 (s, 2H), 7.67 (d, J ¼ 8.7 Hz, 2H), 8.29
(d, J ¼ 8.7 Hz, 2H). 13C NMR (CD3CN) d 15.6, 31.3, 40.9, 69.3, 125.0, 130.1,
143.8, 149.3, 154.8. Anal. calcd. for C11H13N3O5S: C, 48.88; H, 5.22; N,
10.36. Found: C, 49.07; H, 5.31; N, 10.19.

1412
S. Venkata, E. Shamo, and V. Benin
General Procedure for the Preparation of Bis[2-(benzyloxy-
carbonylamino) Ethyl]sulfides (5a,b)
A solution of bis(2-aminoethyl)sulfide (0.50 g, 4.16 mmol) in chloroform
(20 mL) was stirred for 5 min, followed by addition of triethylamine
(0.84 g, 8.33 mmol, 1.16 mL). The resultant mixture was stirred for
10 min at 0 ꢀC, and then a solution of benzyl chloroformate (3a, 1.42 g,
8.33 mmol, 1.18 mL) or 4-nitrobenzyl chloroformate (3b, 1.79 g,
8.33 mmol) in chloroform (10 mL for 3a or 20 mL for 3b) was added
dropwise under nitrogen for about 30 min. The mixture was stirred for
24 h at ambient temperature and vacuum filtered, and the solvent was
removed under reduced pressure. The crude product was further purified
via recrystallization from toluene.
Bis[2-(benzyloxycarbonylamino)ethyl]sulfide (5a)
Recrystallization from toluene yielded 0.73 g (45%) of white solid: mp
93–95 ꢀC. 1H NMR (CD3CN) d 2.61 (t, J ¼ 6.3 Hz, 4H), 3.25
(q, J ¼ 6.3 Hz, 4H), 5.04 (s, 4H), 5.81 (broad s, 2H), 7.28–7.36 (m, 10H).
13C NMR (CD3CN) d 32.5, 41.6, 67.2, 129.0, 129.2, 129.8, 138.7, 157.7.
Anal. calcd. for C20H24N2O4S: C, 61.83; H, 6.23; N, 7.21. Found:
C, 61.73; H, 6.25; N, 7.33.
Bis[2-(4-nitrobenzyloxycarbonylamino)ethyl]sulfide (5b)
The crude reaction product was purified on a short silica-gel column
(ethyl acetate–hexane ¼ 2:1), followed by recrystallization from toluene
1
to yield 0.58 g (29%) of light yellow solid: mp 108–111 ꢀC. H NMR
(CD3CN) d 2.63 (t, J ¼ 6.3 Hz, 4H), 3.29 (m, 4H), 5.16 (s, 4H), 5.94
(broad s, 2H), 7.54 (d, J ¼ 8.7 Hz, 4H), 8.17 (d, J ¼ 8.7 Hz, 4H).
13C NMR (CD3CN) d 32.6, 41.6, 65.9, 124.9, 129.2, 146.6, 148.8,
157.4. Anal. calcd. for C20H22N4O8S: C, 50.20; H, 4.63; N, 11.71. Found:
C, 49.62; H, 4.73; N, 11.38.
General Procedure for the Preparation of Bis[2-(benzyloxycarbonyl-N-
nitrosoamino)ethyl]sulfides (2a,b)
Solid NOBF4 (0.44 g, 3.84 mmol) was added in one portion to a stirred
solution of anhydrous pyridine (0.30 g, 3.84 mmol, 0.31 mL) and
bis[2-(benzyloxycarbonylamino)ethyl]sulfide (5a, 0.50 g, 1.28 mmol) or
bis[2-(benzyloxycarbonyl amino)ethyl]sulfide (5b, 0.62 g, 1.28 mmol) in

Substituted Benzyl N-Nitrosocarbamates
1413
anhydrous acetonitrile (10 mL) at –20 ꢀC. The mixture was stirred at 0 ꢀC
under nitrogen for 4 h, and the progress of the reaction was monitored
by TLC (hexane–ethyl acetate ¼ 2:1). The product exhibited a rapidly
moving yellow spot. The solvent was removed under reduced pressure,
and the crude product in either case was further purified by column
chromatography on silica gel (hexane–ethyl acetate ¼ 2:1).
Bis[2-(benzyloxycarbonyl-N-nitrosoamino)ethyl]sulfide (2a)
1
Yield: 0.23 g (40%) of light yellow liquid. H NMR (CD3CN) d 2.48
(t, J ¼ 6.3 Hz, 4H), 3.85 (t, J ¼ 6.3 Hz, 4H), 5.47 (s, 2H), 7.38–7.47
(m, 10H). 13C NMR (CD3CN) d 28.8, 40.9, 70.9, 129.9, 130.0, 130.1,
136.4, 154.8. Anal. calcd. for C20H22N4O6S: C, 53.80; H, 4.97; N,
12.55. Found: C, 53.94; H, 5.08; N, 12.42.
Bis[2-(4-nitrobenzyloxycarbonyl-N-nitrosoamino)ethyl]sulfide (2b)
1
Yield: 0.27 g (38%) of light yellow liquid. H NMR (CD3CN) d 2.51
(t, J ¼ 6.3 Hz, 4H), 3.88 (t, J ¼ 6.3 Hz, 4H), 5.57 (s, 4H), 7.65
(d, J ¼ 8.7 Hz, 4H), 8.20 (d, J ¼ 8.7 Hz, 4H). 13C NMR (CD3CN) d 28.9,
40.9, 69.3, 125.0, 130.0, 143.7, 149.2, 154.7. HRMS (FABþ) m=z calcd.
for C20H20N6O10S [M þ Na]þ 559.0859; found 559.0856.
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